Biomaterials may be defined as any matter, surface, or construct that interacts with a biological system. Biomaterials are often used in manufacturing of medical devices and dental devices, all of which tend to suffer a common problem of device-related infection. One of the most common device-related infections occurs with dental devices, specifically infections associated with use of biomaterials to treat dental caries.
Dental caries, also known as tooth decay or a dental cavity, is a worldwide pandemic problem caused by a bacterial infection that may lead to progressive demineralization and/or destruction of hard tissues of a tooth. Worldwide, approximately 36% of the population (approximately 2.43 billion people) has dental caries in their permanent teeth. In the United States, dental caries is the most common chronic childhood disease, being at least five times more common than asthma, and is a primary pathological cause of tooth loss in children. Dental caries does not only affect children in the US, as upwards of 60% of adults over the age of fifty experience dental caries. If left untreated, dental caries can lead to pain, tooth loss, and further oral infection. For large lesions, progressive decay can be treated by filing with restorative materials, such as amalgam, composite resin, porcelain and gold. Unfortunately, these filings often have to be redone due to restoration failure, and the site serves as a vulnerable site for further decay and infection.
Secondary caries, also known as recurrent caries, is decay that appears at restoration margins and is a primary cause of restoration failure. Prevention of secondary caries may be attempted through use of fluoride-releasing and/or antibacterial dental materials; however, antibacterial effects of these materials, which may contain releasable reagents (e.g., chlorhexidine), have antibacterial efficacy for only a short time (typically less than about 1 week). Also, these materials often suffer from poor mechanical properties due to porosity in the materials after drug release.
Polymers with antimicrobial (mainly antibacterial and antifungal) activities, generally known as polymeric biocides or antimicrobial polymers, have drawn interest in the fields of biomedical materials and medical implants. See Kenawy E-R et al., The Chemistry and Applications of Antimicrobial Polymers: A State-of-the-Art Review, Biomacromolecules 2007; 8(5):1359-1384. As polymers, the polymeric biocides are more resistent to leaching. Common biocide moieties include quaternary ammonium, pyridinium, phosphonium, and sulfonium salts. The mechanism of action of quaternary compounds may be direct cationic binding to cell wall components, leading to disruption of cell wall membranes, and subsequently leakage of cell contents and cell death. To achieve high antimicrobial efficacy, the quaternary salt typically has at least one long-chain alkyl or substituted alkyl group, and a relatively low tendency to form an ion-pair with a counter ion.
One of the few antibacterial monomers that have been used in dental materials to date is methacryloyloxydodecyl pyrimidinium bromide (MDPB). See Imazato S. et al., Incorporation of bacterial inhibitor into resin composite, Journal of Dental Research 1994; 73:1437-1443; Imazato S, et al., Incorporation of Antibacterial Monomer MDPB into Dentin Primer, Journal of Dental Research 1997; 76:768-772. Bactericidal activity of the monomer and different dental materials (primer, bonding adhesive, and composite) containing MDPB against oral Streptococci have been studied. See Imazato S, et al., Antibacterial Activity and Bonding Characteristics of an Adhesive Resin Containing Antibacterial Monomer MDPB, Dent. Mater. 2003; 19:313-319, and Imazato S., Antibacterial Properties of Resin Composites and Dentin Bonding Systems, Dent. Mater. 2003; 19:449-457. MDPB has been reported to inhibit bacterial growth in uncured resins, in cured resins, and in bonding agents. Incorporating antibacterial activity in a self-etching bonding agent would be of particular clinical importance, because self-etching bonding agents usually have a pH higher than about 2.0, and do not effectively kill acid-resistant bacteria. By contrast, a conventional phosphoric acid (37%) etching gel has pH of 0.8 and effectively kills most bacteria.
Unfortunately, most existing antimicrobial monomers contain only one polymerizable group (usually monomethacrylate), which decreases the overall degree of cross-linking Since the degree of polymerization conversion in dental composite is typically 60%-80%, an uncured antibacterial monomer may leach out reducing antimicrobial effects and mechanical properties. Another drawback of methacrylate-based monomers and polymers is that they are susceptible to hydrolytic and enzymatic degradation, which causes cleavage of ester bonds, and thus deterioration of the materials.
Device-related microbial infections are not limited to dental devices; medical devices are also associated with a definitive risk. Device-related infections, such as catheter-related infections, significantly contribute to an increasing problem of nosocomial, or hospital-acquired, infections. Other medical devices that are prone to device-related infection include prosthetic heart valves, cardiac pacemakers, total artificial hearts, joint replacements or other orthopaedic devices, as well as various shunts and catheters. Collectively, device-related infections are a wide-spread problem with limited preventative options.
Thus, there remains an unmet need for new antimicrobial compounds having improved cross-linking properties and hydrolytic stability, which may lead to sustained long-term antimicrobial efficacy and protection against device-related, microbial infections.